PROJECT SUMMARY Epilepsy negatively impacts quality of life due to the seizure burden and associated depression and anxiety, in addition to increased morbidity and mortality. Temporal lobe epilepsy (TLE) is one of the most common forms of focal epilepsy. Anti-epileptic medication is successful in treating about 60-70% of these patients. In the remaining patients, usually after long, unsuccessful drug trials, surgical intervention of the presumed seizure focus leads to seizure freedom in 50-80% of patients. Therefore, more accurate early predictors of pharmacological and surgical treatment outcome are needed to improve clinical management of these patients. The scientific premise of this work is that while the identification of the seizure focus plays an important role in directing management of focal epilepsy patients, the outcome of treatment (pharmacological and surgical) is significantly influenced by the connectivity across large widespread network(s).Therefore, the goal of this project is to develop early biomarkers of drug responsiveness and surgical outcome using MRI functional and structural connectivity quantification. In a homogeneous group of drug refractory mesial TLE patients whose seizure focus was presumed to be the hippocampus based on current clinical assessments, the relationship between resting-state functional and structural network integrity in seizure propagation networks were quantified non-invasively using MRI. These network alterations were related to disease and cognitive characteristics before and after surgery. This allowed the development of a preliminary MRI connectivity biomarker for post-surgical seizure outcome in mesial TLE. Building on this foundation, the specific aims of this proposal will result in the improvement of functional and structural connectivity biomarkers of surgical outcome in mesial TLE (Aim 1), and the development of similar biomarkers for use in other TLE patients with seizures originating in the temporal lobe outside the mesial temporal structures (Aim 2). The success of Aim 3 will provide a method for early identification of those who will and will not respond to anti- epileptic medication to reduce prolonged drug trials. The overall outcome of this work will directly address the 2014 NINDS Benchmarks for Epilepsy Research section III part B: to identify biomarkers for assessing or predicting treatment response, including markers that may identify specific populations that are likely to have good outcomes or develop adverse responses. As such, this study has the potential to result in significantly improved clinical management of a common debilitating disorder.